Distinct cardiac and renal effects of ET_Areceptor antagonist and ACE inhibitor in experimental type 2 diabetes

Abstract

Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF.

Aging and the Renin-Angiotensin System

“…Animal and human data supporting such effects of Ang II blockers in nondiabetic and diabetic renal disease are overwhelming. [19][20][21][22][23] Concerning the brain, studies indicate that Ang II inhibitors mitigate progressive cognitive decline associated with aging, as well as with various neurodegenerative disorders. Recent studies show that Ang II inhibitors help to preserve cognitive functions in patients with Alzheimer disease through a mechanism that is independent of the blood pressure-lowering effect.…”

Endothelin-1 Gene Polymorphisms rs5370, rs1476046, and rs3087459 are not Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus

“…47 In contrast, blockade of ET-1 signaling revealed renoprotective effects in experimental models of DN, independent of blood pressure reduction 12 , with a decrease in proteinuria, and evidence of reduced glomerulosclerosis. 11 In addition, anti-infl ammatory effects of ET receptor antagonists resulted in reduced expression of intercellular adhesion molecule 1 and MCP-1 48 , as well as reduced renal monocyte infi ltration and expression of proinfl ammatory cytokines in different models of DN 49,50 . Atrasentan, a selective ETA receptor antagonist, was effi cacious in lowering residual albuminuria in subjects with T2DM on stable doses of RAS inhibitors.…”

Cardiovascular risk and stress adaptation in metabolic diseases

“…A third group of differentially expressed metabolic genes in our present study (down-regulation of argininosuccinate synthetase and up-regulation of angiopoietin-like 4) in ZDF hearts is potentially regulated by oxidative and nitrative stress which is increased in metabolic diseases e.g. hyperlipidemia [133], hypertension [134], insulin resistance [135], diabetes mellitus [136] and in the heart of ZDF rats as well [103]. High TNF-alpha concentrations [137] and insulin resistance [138,139] in endothelial cells have been reported to reduce the expression of the arginine recycling enzyme, argininosuccinate synthetase.…”

“…To verify the well-known increased oxidative/nitrative stress [102,103] in the heart in metabolic syndrome, cardiac free 3-nitrotyrosine level, an indirect marker of nitrative stress, was measured by ELISA (Cayman Chemical) from ZDF and lean control heart tissue samples at week 25 as described earlier [11]. Briefly, supernatants of ventricular tissue homogenates were incubated overnight with anti-nitrotyrosine rabbit IgG specific to free 3-nitrotyrosine and nitrotyrosine acetylcholinesterase tracer in precoated (mouse anti-rabbit IgG) microplates followed by development with Ellman's reagent.…”